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A Simple Methodology to Differentiate Changes in Bioavailability From Changes in Clearance Following Oral Dosing of Metabolized Drugs.
Clinical Pharmacology & Therapeutics ( IF 6.3 ) Pub Date : 2020-03-09 , DOI: 10.1002/cpt.1828
Jasleen K Sodhi 1 , Leslie Z Benet 1
Affiliation  

Accurately discriminating changes in clearance (CL) from changes in bioavailability (F ) following an oral drug–drug interaction is difficult without carrying out an intravenous interaction study. This may be true for drugs that are clinically significant transporter substrates; however, for interactions that are strictly metabolic, it has been recognized that volume of distribution remains unchanged between both phases of the interaction study. With the understanding that changes in volume of distribution will be minimal for metabolized drugs, the inverse of the change in apparent volume of distribution can provide adequate estimates of the change in bioavailability alone. Utilization of this estimate of F change in tandem with the observed apparent clearance (CL/F ) change in an oral drug–drug interaction can provide an estimate of the change in clearance alone. Here, we examine drug–drug interactions involving five known inhibitors and inducers of cytochrome P450 3A4 isozyme on victim drugs midazolam and apixaban for which the interaction was carried out both orally and intravenously, allowing for evaluation of this methodology. Predictions of CL and F changes based on oral data were reasonably close to observed changes based on intravenous studies, demonstrating that this simple yet powerful methodology can reasonably differentiate changes in F from changes in CL for oral metabolic drug interactions when only oral data are available. Utilization of this relatively simple methodology to evaluate DDIs for orally dosed drugs will have a significant impact on how DDIs are interpreted from a drug development and regulatory perspective.

中文翻译:

一种区分生物利用度变化与代谢药物口服给药后清除率变化的简单方法。

如果不进行静脉相互作用研究,就很难准确区分口服药物相互作用后清除率 (CL) 的变化和生物利用度 ( F ) 的变化。对于具有临床意义的转运蛋白底物的药物来说,这可能是正确的。然而,对于严格代谢的相互作用,已经认识到在相互作用研究的两个阶段之间分布容积保持不变。认识到代谢药物的分布容积变化将是最小的,表观分布容积变化的倒数可以单独提供对生物利用度变化的充分估计。利用这种F变化估计值与观察到的表观清除率 (CL/ F) 口服药物-药物相互作用的变化可以单独估计清除率的变化。在这里,我们研究了涉及五种已知抑制剂和细胞色素 P450 3A4 同工酶诱导剂的药物相互作用,这些抑制剂和诱导剂对受害药物咪达唑仑和阿哌沙班进行了口服和静脉注射,从而可以评估这种方法。基于口服数据对 CL 和F变化的预测与基于静脉研究观察到的变化相当接近,表明这种简单而强大的方法可以合理区分F 的变化当只有口服数据时,口服代谢药物相互作用的 CL 变化。使用这种相对简单的方法来评估口服药物的 DDI 将对如何从药物开发和监管角度解释 DDI 产生重大影响。
更新日期:2020-03-09
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